Our laboratory uses biochemical, genetic, and transgenic methods to understand the normal and oncogenic properties of several genes implicated in neoplasia. Current activities address the following issues: (1) Wnt gene signaling. The secretory glycoproteins encoded by the Wnt gene family govern a wide array of developmental and oncogenic phenomena. We are using reporter assays in mammalian cell culture, gene array technology, and morphological assays in Xenopus to define the roles of the many positively- and negatively-acting factors recently implicated in the Wnt signaling pathway. (2) Multi-step tumorigenesis. Over the past several years, we have used MMTV-Wnt-1 transgenic mice to identify proto-oncogenes (mainly members of the FGF family), tumor suppressor genes (p53), and hormonal factors (estrogen receptor) that influence the development and the properties of mammary carcinomas. More recently, we have also been producing models for human cancer by programming mice to express the receptor (TVA) for certain avian retroviruses in a tissue-specific manner. For example, we have induced many of the histological features of human glioblastomas by recapitulating the genetic lesions found in those tumors in mice expressing TVA in the glial lineage. Similar studies are now underway to generate models for cancers of the breast, lung, ovary and other organs. (3) Cell cycle regulators and cancer. We have been cataloging and characterizing mutant forms of p16, an inhibitor of Cdk/cyclin complexes, and of Cdk4 that contribute to familial and sporadic melanomas. In addition, we are examining the effects of these cell cycle regulators, which are often deranged in human gliomas, using cultured astrocytes. (4) The functions of protein-tyrosine kinases. Over the past several years, we have studied members of three families of tyrosine kinases: (a) Src, Hck, and other members of the Src family that have demonstrated functions in osteoclasts and fibroblasts from genetically altered mice; (b) Sky (Tyro 3), a recently discovered, receptor-type protein-tyrosine kinase from the Axl family, that is abundant in normal brain and mouse mammary tumors, and can function in the plasma membrane or cytoplasm; and (c) Rlk, a newly discovered member of the Btk/Itk family, expressed exclusively in T cells, where it has a role in signal transduction and cytokine production. - Animal models, Cancer cell growth regulation, Proto-oncogenes, Tumor Suppressor,